title: A role for antibodies to human leukocyte antigens, collagen-V, and K-α1-Tubulin in antibody-mediated rejection and cardiac allograft vasculopathy.
abstract: BACKGROUND
  We determined the role of donor-specific antibodies (DSA) and antibodies (Abs) to self-antigens, collagen-V (Col-V), and K-α1-Tubulin (KAT) in pathogenesis of acute antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) after human heart transplantation (HTx).
  
  
  METHODS
  One hundred thirty-seven HTx recipients, with 60 early period (≤ 12 months) and 77 late period (>12 months), were enrolled in this study. Circulating DSA was determined using LUMINEX. Abs against Col-I, II, IV, V, and KAT were measured using ELISA. Frequency of CD4+T helper cells (CD4+Th) secreting interferon (IFN)-γ, interleukin (IL)-5, -10, or -17 specific to self-antigens were determined using Enzyme Linked Immunosorbent Spot assay.
  
  
  RESULTS
  A significant association between AMR and DSA was demonstrated. Development of DSA in AMR patients correlated well with the development of auto-Abs to Col-V (AMR[+]: 383 ± 72 μg/mL, AMR[-]: 172 ± 49 μg/mL, P=0.033) and KAT (AMR[+]: 252 ± 49 μg/mL, AMR[-]: 61 ± 21 μg/mL, P=0.014). Patients who developed AMR demonstrated increased frequencies of CD4+Th secreting IFN-γ and IL-5 with reduction in IL-10 specific for Col-V/KAT. Patients diagnosed with CAV also developed DSA and auto-Abs to Col-V (CAV[+]: 835 ± 142 μg/mL, CAV[-]: 242 ± 68 μg/mL, P=0.025) and KAT (CAV[+]: 768 ± 206 μg/mL, CAV[-]: 196 ± 72 μg/mL, P=0.001) with increased frequencies of CD4+Th secreting IL-17 with reduction in IL-10 specific for Col-V/KAT. CONCLUSIONS.: Development of Abs to human leukocyte antigens and self-antigens are associated with increases in CD4+Th secreting IFN-γ and IL-5 in AMR and IL-17 in CAV, with reduction in CD4+Th secreting IL-10 in both AMR and CAV.
authors.affiliation: Division of Cardiothoracic Surgery, Washington UniversitySchool of Medicine, St. Louis, MO 63110, USA.
authors.forename: Dilip S
authors.initials: DS
authors.lastname: Nath
authors.forename: Venkataswarup
authors.initials: V
authors.lastname: Tiriveedhi
authors.forename: Haseeb Ilias
authors.initials: HI
authors.lastname: Basha
authors.forename: Donna
authors.initials: D
authors.lastname: Phelan
authors.forename: Nader
authors.initials: N
authors.lastname: Moazami
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Ewald
authors.forename: Thalachallour
authors.initials: T
authors.lastname: Mohanakumar
mesh_terms: D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000276:immunology; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000276:immunology*; D024062:Collagen Type V / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000209:etiology* / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology*; D016027:Heart Transplantation / Q000009:adverse effects* / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D007518:Isoantibodies / Q000097:blood*; D008297:Male; D008875:Middle Aged; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014404:Tubulin / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D024062:Collagen Type V; D006680:HLA Antigens; C508609:IL10 protein, human; C508599:IL5 protein, human; D015848:Interleukin-5; D007518:Isoantibodies; D014404:Tubulin; D016753:Interleukin-10; D007371:Interferon-gamma